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Dive into the research topics where Alan Hutchison is active.

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Featured researches published by Alan Hutchison.


British Journal of Pharmacology | 1988

Characterization of the binding of [3H]-CGS 19755: a novel N-methyl-d-aspartate antagonist with nanomolar affinity in rat brain

Deborah Murphy; Alan Hutchison; Steven D. Hurt; Michael Williams; Matthew A. Sills

1 CGS 19755 (cis‐4‐phosphonomethyl‐2‐piperidine carboxylic acid), a rigid analogue of 2‐amino‐5‐phosphonopentanoic acid (AP5), is one of the most potent competitive N‐methyl‐d‐aspartate (NMDA) antagonists described. Using Triton‐treated crude synaptic membranes from rat brain, binding studies indicated that [3H]‐CGS 19755 bound with high affinity and selectivity to the NMDA‐type excitatory amino acid receptor. 2 [3H]‐CGS 19755 binding was saturable, reversible, heat‐labile, pH‐dependent and linear with protein concentration. Specific binding represented 80–85% of the total amount bound. 3 Using a centrifugation assay, saturation experiments revealed two distinct binding components with Kd values of 9 and 200 nM, and corresponding Bmax values of 0.55 and l.00 pmol mg−1 protein. In contrast, a single binding component with a Kd value of 24 nM and an apparent value of 0.74 pmol mg−1 protein was observed with a filtration assay. 4 Competition experiments in which both assay techniques were used, showed that [3H]‐CGS 19755 selectively labels the NMDA receptor. The most active inhibitors of [3H]‐CGS 19755 binding were l‐glutamate and CGS 19755 (IC50 values = 100 nm). 5 In the centrifugation assay, a number of excitatory amino acids were found to generate shallow inhibition curves, and computer analysis indicated the presence of two binding components. The quisqualate receptor ligand AMPA (D,L‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate), kainic acid and the non‐competitive NMDA antagonists, such as phencyclidine, tiletamine and MK‐801, were without activity. 6 The high affinity binding obtained with [3H]‐CGS 19755 by use of filtration techniques thus permits the more rapid evaluation of compounds as potential NMDA antagonists and agonists. Therefore, this rigid analogue of AP5 is a more suitable radioligand for NMDA receptors than [3H]‐CPP (3‐(±)−(2‐carboxypiperazin‐4‐yl)propyl‐l‐phosphonic acid), the corresponding analogue of 2‐amino‐7‐phosphonoheptanoic acid (AP7).


Bioorganic & Medicinal Chemistry Letters | 2002

Indoline and piperazine containing derivatives as a novel class of mixed D2/D4 receptor antagonists. Part 1: Identification and structure–activity relationships

He Zhao; Andrew Thurkauf; Xiao-shu He; Kevin J. Hodgetts; Xiaoyan Zhang; Stanislaw Rachwal; Renata X. Kover; Alan Hutchison; John R. Peterson; Andrzej Kieltyka; Robbin Brodbeck; Renee J. Primus; Jan W. F. Wasley

Optimization of the lead compound 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2,3-dihydro-indol-1-yl)-ethanone 1 by systematic structure-activity relation (SAR) studies lead to two potent compounds 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 2n and 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 7b. Their related synthesis was also reported.


Journal of Biological Chemistry | 2005

Molecular Characterization of the Gerbil C5a Receptor and Identification of a Transmembrane Domain V Amino Acid That Is Crucial for Small Molecule Antagonist Interaction

Stephen M. Waters; Robbin Brodbeck; Jeremy Steflik; Jianying Yu; Carolyn Baltazar; Amy E. Peck; Daniel Severance; Lu Yan Zhang; Kevin P. M. Currie; Bertrand L. Chenard; Alan Hutchison; George Maynard; James E. Krause

Anaphylatoxin C5a is a potent inflammatory mediator associated with pathogenesis and progression of several inflammation-associated disorders. Small molecule C5a receptor (C5aR) antagonist development is hampered by species-specific receptor biology and the associated inability to use standard rat and mouse in vivo models. Gerbil is one rodent species reportedly responsive to small molecule C5aR antagonists with human C5aR affinity. We report the identification of the gerbil C5aR cDNA using a degenerate primer PCR cloning strategy. The nucleotide sequence revealed an open reading frame encoding a 347-amino acid protein. The cloned receptor (expressed in Sf9 cells) bound recombinant human C5a with nanomolar affinity. Alignment of the gerbil C5aR sequence with those from other species showed that a Trp residue in transmembrane domain V is the only transmembrane domain amino acid unique to small molecule C5aR antagonist-responsive species (i.e. gerbil, human, and non-human primate). Site-directed mutagenesis was used to generate human and mouse C5aRs with a residue exchange of this Trp residue. Mutation of Trp to Leu in human C5aR completely eliminated small molecule antagonist-receptor interaction. In contrast, mutation of Leu to Trp in mouse C5aR enabled small molecule antagonist-receptor interaction. This crucial Trp residue is located deeper within transmembrane domain V than residues reportedly involved in C5a- and cyclic peptide C5a antagonist-receptor interaction, suggesting a novel interaction site(s) for small molecule antagonists. These data provide insight into the basis for small molecule antagonist species selectivity and further define sites critical for C5aR activation and function.


Journal of Pharmacology and Experimental Therapeutics | 2008

Identification and characterization of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a novel, orally bioavailable C5a receptor inverse agonist.

Robbin Brodbeck; Daniel N. Cortright; Andrzej Kieltyka; Jianying Yu; Carolyn Baltazar; Marianne E. Buck; Robin Meade; George Maynard; Andrew Thurkauf; Du-Shieng Chien; Alan Hutchison; James E. Krause

The complement system represents an innate immune mechanism of host defense that has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the biological activity of C5a and its classical receptor have been widely studied. Because specific antagonism of the C5aR could have therapeutic benefit without affecting the protective immune response, the C5aR continues to be a promising target for pharmaceutical research. The lack of specific, potent and orally bioavailable small-molecule antagonists has limited the clinical investigation of the C5aR. We report the discovery of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a small-molecule, orally bioavailable, selective, and potent inverse agonist of the human C5aR. NDT 9513727 was discovered based on the integrated use of in vitro affinity and functional assays in conjunction with medicinal chemistry. NDT 9513727 inhibited C5a-stimulated responses, including guanosine 5′-3-O-(thio)triphosphate binding, Ca2+ mobilization, oxidative burst, degranulation, cell surface CD11b expression and chemotaxis in various cell types with IC50s from 1.1 to 9.2 nM, respectively. In C5a competition radioligand binding experiments, NDT 9513727 exhibited an IC50 of 11.6 nM. NDT 9513727 effectively inhibited C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. The findings suggest that NDT 9513727 may be a promising new entity for the treatment of human inflammatory diseases.


Bioorganic & Medicinal Chemistry Letters | 2008

Aminopyrazine CB1 receptor inverse agonists.

David Juergen Wustrow; George D. Maynard; Jun Yuan; He Zhao; Jianmin Mao; Qin Guo; Mark T. Kershaw; Jack Hammer; Robbin Brodbeck; Kristen E. Near; Dan Zhou; David S. Beers; Bertrand L. Chenard; James E. Krause; Alan Hutchison

A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.


Annual Reports in Medicinal Chemistry | 2004

The Discovery of Small Molecule C5a Antagonists

Alan Hutchison; James E. Krause

Publisher Summary In host defense, the complement system of blood-borne proteins initiates a series of cellular and inflammatory responses to divergent stimuli. Excessive activation of the complement system in man results in elevated C5a, a glycosylated 74-amino acid protein, that is associated with several acute and chronic clinical situations or disease states. C5a receptor antagonists have been proposed to be useful in rheumatoid arthritis, respiratory distress syndrome, ischemia-reperfusion injury, sepsis, psoriasis, and inflammatory bowel disease. This chapter provides an overview of the complement pathway in man and the role of the C5a effector arm in anaphylatoxin biology. Recent work on the identification of peptide and small molecule C5a receptor antagonists is summarized. The generation of small molecule C5a antagonists has been a recalcitrant problem for medicinal chemists. However, recent reports suggest that several blueprints now exist for the potential solution of this elusive problem. At least two orally bioavailable small molecule C5a antagonists are reported to be in Phase II clinical trials: NGD 2000-1 and PMX53. Preliminary reports of the efficacy of PMX53 in psoriasis have been reported.


Bioorganic & Medicinal Chemistry Letters | 2008

1-Benzylbenzimidazoles: The discovery of a novel series of bradykinin B 1 receptor antagonists

Qin Guo; Jayaraman Chandrasekhar; David C. Ihle; David Juergen Wustrow; Bertrand L. Chenard; James E. Krause; Alan Hutchison; Dawn Alderman; Charles S. Cheng; Daniel N. Cortright; Daniel Broom; Mark T. Kershaw; Jean Simmermacher-Mayer; Yao Peng; Kevin J. Hodgetts

The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.


Bioorganic & Medicinal Chemistry Letters | 2008

2-Arylpyrimidines : Novel CRF-1 receptor antagonists

Taeyoung Yoon; Stéphane De Lombaert; Robbin Brodbeck; Michael Gulianello; James E. Krause; Alan Hutchison; Raymond F. Horvath; Ping Ge; John H. Kehne; Diane Hoffman; Jayaraman Chandrasekhar; Dario Doller; Kevin J. Hodgetts

The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.


Archive | 2001

Capsaicin receptor ligands

Rajagopal Bakthavatchalam; Alan Hutchison; Robert W. DeSimone; Keven J. Hodgetts; James E. Krause; Geoffrey White


Archive | 2001

SPIRO ISOBENZOFURAN-1,4'-PIPERIDIN]-3-ONES AND 3H-SPIROISOBENZOFURAN-1,4'-PIPERIDINES

Rajagopal Bakthavatchalam; Charles A. Blum; Harry Brielmann; James W. Darrow; Stéphane De Lombaert; Alan Hutchison; Jennifer Tran; Xiaozhang Zheng; Richard Louis Elliott; Marlys Hammond

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